Condensation reactions in dimethyl sulfoxide solution and sulfoxides



3,256,340 CONDENSATION REACTIONS IN DIMETHYL SULFOXIDE SOLUTION ANDSULFOXIDES Glen A. Russell, Dept. of Chemistry, Iowa State University,Ames, Iowa No Drawing. Filed May 13, 1963, Ser. No. 280,109 9 Claims.(Cl. 260-607) This invention relates to a process for the condensationof dimethyl sulfoxide with aldehydes and ketones. It further relates tothe condensation of aromatic aldehydes with active methylene compounds.It is also concerned with the intermediates and ultimate product-sobtained by these processes.

One of the principal objects of the present invention is to provide anovel type of condensation reaction, whereby valuable new productsresult. The final prod ucts are variously useful as, for instance,chelating agents for metal ions, as intermediates in olefin syntheses,and in high melting polymeric systems. The sulfoxides are valuableintermediates for the synthesis of sulfur-free compounds because oftheir ability to:

(l) Undergo pyrolysis (2)To form sulfones which can undergo eliminationin the presence of base B GHCHzSOzCH; C=OH1 CHBSOECH! (3) To undergo thePummerer rearrangement with strong acids CHGHzSOGHa HX Other objects andadvantages of this invention will become apparent from the ensuingdisclosure and claims. These objects are realized by the presentinvention, which in its broader aspects comprises condensing an aromaticcompound with an active methylene compound in an alkaline solvent mediumcomprising dimethyl sulfoxide and a strong base. In a preferred firststep of the process, the aromatic-compound is simply dissolved in thealkaline medium at a relatively low temperature to form an adduct withthe dimethyl sulfoxide itself. This adduct is then dehydrated to providean unsaturated sulfoxide, and this latter compound is then condensedwith the desired active methylene compound, again in an alkaline mediumcomprising dimethyl sulfoxide and a strong base. According to a secondpreferred embodiment of the invention, an aromatic aldehyde is reacteddirectly with the desired active methylene compound in the alkalinesolvent medium comprising DMSO (dimethyl sulfoxide) and the strong base.

According to still more specific embodiments of the invention, it hasfirst of all been found that dimethyl sulfoxide readily forms 1:1adducts with aromatic ketones and aldehydes, such as benzaldehyde,fluorenone, benzophenone and anthraquinone, in the presence of alkoxideions, e.g. t-butoxide ion, and in the presence of excess DMSO orDMSO-.t-butyl alcohol mixtures as solvents. The compounds thus formedare new and have 4 the structure wherein'R is an aromatic radical and Ris either hydrogen or an aromatic radical.

Next, it has been found that aromatic aldehydes (RCHO) will react inDMSO solution in the presence United States Patent of strong bases suchas potassium t-butoxide with active methylene compounds (RR"CH such asdiphenylmethane, to yield new sulfoxides of the structure RR"CHCHR-CHSOCH wherein R,R' and R" are each selected from the group consisting ofphenyl and substituted phenyl. These sulfoxides can be converted to thecorresponding sulfones by treatment with hydrogen peroxide or tovaluable olefins, like the corresponding 1,1,2-tri-substituted propeneby the action of strong base, or the 2,3,3-trisubstituted propene isomerby thermal decomposition.

Third, it has been found that active methylene compounds of the typeR'CH wherein R is a substituted phenyl, such as phenyl-p-tolylsulfone,will condense with aromatic aldehydes (RCHO) in DMSO-t-butyl alcoholsolution, again in the presence of a strong base, to give a wide varietyof stilbene derivatives The dimethyl sulfoxide addncts are of courseuseful as intermediates for the subsequent condensation with the activemethylene com-pounds. They are also useful per se as chelating agentsfor metal ions, particularly in their oxidized form RCOCH SOCH or RCOCHSO CH The condensates with the active methylene compounds of the typeR'R"CH and the related products of the type R'R"CH-CHR-CH SO CH areuseful intermediates in the preparation of olefins. For instance, theycan be converted readily with heat and/or alkaline conditions to olefinssuch as RR"CHCH=CH and RR"=C=CHR.

Other valuable specific compounds, prepared according to the processesof this invention, are:

The three preferred condensation reactions of this invention can bewritten mechanistically:

I RC HCHzSOCH and RCHO CHQSOCHQ The heart of the present inventionresides in the use of dimethyl sulfoxide as a major part of the reactionmedium wherein the aromatic aldehydes and ketones are condensed, and inthe presence in this medium of a strong base. Provided these criticallimitations are met, a wide variation is readily possible in the otheroperating conditions such as temperatures, times, aldehydes and ketonesand active methylene compounds being interreacted, etc. The usefulaldehydes and ketones are those which are aromatic in nature and have noionizable (acidic) alpha-hydrogenation. Generally preferred are benzenederivatives, for instance benzene itself, naphthalene and anthracenederivatives.

The useful active methylene compounds have either the formula R'CH orthe formula R'R"CH In both of these classes of compounds the R and R"are either phenyl per se or substituted phenyl, for instance diphenylmethane, ditolyl methane, phenyl p-tolyl sulfone, mono phenyl-monotolyl.methane, cyclohexanone and acetophenone.

As usual in chemical reactions, the reaction times and temperatures areinterdependent and may readily be adjusted by those skilled in the art,depending on the reactants employed. It is generally preferred tooperate all of the condensation steps at temperatures substantiallybetween 20 and 80 C. For the initial formation of the dimethyl sulfoxideadduct, temperatures between about 20 and 80 C., particularly 20 to 40C., are usually sufficient. Elevated temperatures are employed, forinstance between about 50 and 70 C., to dehydrate such an adduct andobtain the corresponding unsaturated sulfoxide. For direct condensationof the aromatic aldehyde with the active methylene compound,particularly satisfactory temperatures range between about 30 and 60 C.,while for condensing the aldehyde sulfoxide with the active methylenecompound, somewhat lower temperatures, from about 20 to 40 C., arenormally suificient. Depending upon the particular temperature and theparticular operation, the times for complete reaction may vary anywherefrom about 5 minutes to about 4 hours. Generally the adduct formationproceeds rapidly, say in to 30 minutes, dehydration of the adduct takesfrom 1 to 2 hours, and condensation with the active methylene compoundsrequires from /2 to 2 hours.

The solvent medium in which the condensation reactions take place may bemade alkaline by use of a number of different types of strong bases.Particularly valuable are the alkali metal oxides, hydroxides, hydridesand alkoxi-des, as well as the alkali metals themselves, e.g. sodium,potassium and lithium methoxides, ethoxides, propoxides and butoxides,the corresponding hydrides, hydroxides and oxides. Preferred proportionsof the alkali metal compound range from about 0.1 to 3.0 moles per moleof the aromatic aldehyde to be reacted. Dimethyl sulfoxide may be usedalone in excess both as the solvent medium and as the reactant. In manycases, however, up to about 50% by volume, and usually from 10 to 25%,of the medium may be tertiary butyl alcohol. The use of tertiary butylalcohol as a co-solvent is advantageous since it stabilizes the basicsolution from reaction with oxygen. Operable solvent constituents inlieu of the tertiary butanol are other alcohols such as methanol,ethanol, and tertiary alcohols in general.

The following examples are given simply to illustrate this invention andnot in any way to limit its scope.

Example I To a solution of 1.7 grams (10' mole) of diphenylmethane inmilliliters of dimethyl sulfoxide under a blanket of nitrogen at atemperature of 60 C. were added 1.34 grams (1.2)(10?) of potassiumtertiary butoxide that had been purified by sublimation in vacuum. Theresulting solution was orange-red in color.

A solution of 1.4 grams (10' mole) of p-anisaldehyde in 5 milliliters ofdimethyl sulfoxide at a temperature of 40 C. was gradually added to thefirst solution over a period of 4 minutes, also under the blanket ofnitrogen. The resulting solution first turned to a deep red color, butchanged to green after completion of the addition of all of theanisaldehyde. This combine solution was maintained at 40 C., whileblanketed with nitrogen, for

an additional period of 2 hours, after which water containing ice wasadded. The mixture containing precipitated solids was then shaken with30 milliliters of ether and the solids separated by filtration. In thismanner 2.0 grams, equivalent to 50 percent of the stoichiometric yield,of colorless crystals were obtained. These crystals, afterrecrystallization from hot ethanol, had a melting point of 178180 C.From the filtered aqueous phase, an additional 500 milligrams of impureproduct were obtained by extraction with ether.

The infrared spectrum, integrated nuclear magnetic resonance spectrum,molecular weight, and elemental analyses for carbon, hydrogen, andsulfur, results of some of which are included hereinbelow, as well asdegradation reactions and oxidation to a sulfone, that are describedhereinafter, support the following formula for this product:

OCH:

Analysis (percentages by weight).Found: C, 757.78; H, 6.94; S, 8.94.Molecular weight (dioxane), 380. Calculated for C H O S: C, 75.80; H,6.64; S, 8.78. Molecular weight, 364.6.

Substitution of cyclohexanone for the diphenylmethane in this reaction,on an equivalent molar basis, produced the sulfoxide:

OCH

Recrystallization from ethanol by the addition of a little chloroformgave M.P. 275-6". The IR and NMR spectra were consistent with the abovestructure. The NMR spectrum failed to show a methyl group other thanthat of the p-methoxy group.

Analysis.Calculated for C H O S (294.34): C, 65.29; H, 7.53; S, 10.82.Found: C, 65.31; H, 7.69; S, 11.00.

Example II with about 50 milliliters of ether. A precipitate of 0.185

gram of l-(methylsulfinyl)-2-p-methoxyphenyl-3,3-diphenylpropene wasremoved by filtration. The aqueou layer was extracted with 700 ml. ofether. Evaporation of the ether yielded an oil which crystallized whentreated with a trace of ethanol to yield 2.09 grams of crystals, M.P.103-4, of 1,l-diphenyl-Z-(p-methoxyphenyl)-propene-l yield). It has theformula hereinbelow, as shown by its infrared and integrated nuclearmagnetic resonance spectra, its molecular weight and its elementalanalysis. 4

OCH3

t=am Analysis-Found: C, 88.07; H, 6.86. Molecular weight (dioxane), 313.Calculated for C H O: C, 87.96; H, 6.71. Molecular weight, 300.4.

Example 111 The same propene1-derivative of Example II was also obtainedby treating the corresponding dimethyl sulfoxide adduct as follows:

Three hundred mg. of the product of Example I were dissolved in amixture of 4 ml. of dimethyl sulfoxide and 1 ml. of t-butyl alcohol at60 C. under nitrogen, and 112 mg. potassium t-butoxide were added. Afterstanding at 6065 C. for one hour, the reaction mixture was kept at roomtemperature for 3.5 hours, and then again kept at 60 for 0.5 hour. Then50 ml. of water were added together with 50 ml. of ether. The mixturewas shaken and filtered, leaving unreacted starting material as anether-insoluble residue. From the ether solution 118 mg. of1,1-diphenyl-2-(p-methoxyphenyl)-pro pene-l crystallized afterevaporation of the solvent. Its infrared absorption spectrum wasidentical with that of an authentic sample (yield 46.5%).

An isomer of this product was also obtained by pyrolysis of thesulfoxide product of Example. I, as follows:

Four hundred mg. of the product of Example I were treated in an oil bathunder -20 mm. pressure at 200- 220 C. for 17 minutes, at the end ofwhich time the gas evolution had ended. The colorless oily residue wasdissolved in 8 ml. of a mixture of. chloroform and ethyl alcohol and thesolution filtered. After standing overnight, 300 mg. of3,3-diphenyl-2-(p-methoxyphenyl)-propene-1 was isolated as colorlesscrystals, M.P. 71 C., yield 91% This compound had the structure:

Analysis.Calculated for C H O: C, 87.96; H, 6.71; OCH 10.33. Found: C,88.03; H, 6.63; OCH 10.03.

It reacts readily with bromine in chloroform. The NMR spectrum supportsthis structure since the terminal methylene group is readily apparent.

Example IV p-Anisaldehyde, 1.36 g. (1 10 mole) was dissolved in excessdimethyl sulfoxide (12 ml.) containing 3 ml. of t-butyl alcohol and 1.12grams of potassium tertiary butoxide. The mixture was maintained in aninert atmosphere at 25 C. for 1 hour. The resulting 1:1 dimethylsulfoxide :adduct and the formula R CHOHCH SOCH R being p-methoxyphenyl.It was isolated in yield, M.P. 129-131", on recrystallization from hotethanol.

Analysis.Calcd. for C I-I O S (214.21): C, 56.07; H, 6.59; S, 14.91.Found: C, 56.09; H, 6.46; S, 15.10.

This process was repeated, substituting piperonal in the same molarproportion for the p-anisaldehyde, and

holding the mixture at 30 C. for 45 minutes. The corresponding adduct (R:being 3,4-methylenedioxyphenyl) was obtained in 21% yield, meltingpoint 160 C.

Analysis.Calcd. 0 11 0 3 (228.20): c, 52.63; H, 5.30; S, 14.0. Found: C,52.44; H, 5.53; S, 14.21.

Example V The p-anisaldehydezdimethyl sulfoxide adduct (53 mg.) ofExample IV was returned to an alkaline medium consisting of 56 mg. ofpotassium t-butoxide in 2 ml. of dimethyl sulfoxide and heated at 60 C.for 10 minutes. The resulting unsaturated sulfoxide, obtained in 47%yield, had the formula R CH=CHSOCH (R being p-methoxyphenyl); meltingpoint 67-68 C.

Example VI To a solution of potassium t-butoxide (560 mg.) in 10 cc. ofDMSO at room temperature, 0.7 cc. (5 mmoles) of p-anisaldehyde was addeddropwise under an atmosphere of dry, prepurified nitrogen at roomtemperature. The solution was warmed to 60-65 for 80 minutes. After thistime 100 cc. of water was added to the brown solution to yield anemulsion. The emulsion was extracted with 500 ml. of other, the etherextract dried over sodium sulfate and evaporated to yield a light yellowoily residue that crystallized upon treatment with a little ether togive 450 mg. (46%) of B-methylsulfinyU- p-methoxystyrene in the form offine, colorless needles, M.P. Recrystallization from ether raised theM.P. to 67-68 C.

Analysis.Calcd. C H O S (196.20): C, 61.21; H, 6.17; S, 16.31. Found: C,61.11; H, 6.33; S, 16.00.

Example VII The condensation of 1.7 gram (1X10- mole) diphenylmethaneand 1.0 grams (1 10- mole) benzaldehyde in 15 ml. of dimethyl sulfoxidecontaining 1.12 grams potassium t-butoxide, at 60 C. for 15 minutesfollowed by 30 minutes at room temperature, yielded colorless crystalsof the following sulfoxide, M.P. 195- 196 C.

Analysis.-Calcd. C H OS: C, 79.01;- H, 6.63; S, 9.57. Found: C, 78.98;H, 6.72; S, 9.21.

An oil was also obtained which upon heating with ethanol yields 430 mg.of 1,1,2-triphenylpropene-1, M.P. 88-89 C.

Example VIII The initial product of Example VII (200 mg., 0.6 mmole) washeated under aspirator vacuum in oil bath at 220-225 for 15 minutes. Gasevolution ceased after 5 minutes. The almost colorless oil whichremained was dissolved in 2 cc. of warm ethanol to yield 96 mg.

(61%) of colorless 2,3,3-triphenyl-1-propene, M.P. 49- 50, afterevaporation of solvent.

Analysis. Calcd. for C H (270.35): C, 93.29; H, 6.71. Found: C, 93.10;H, 6.76.

Exam ple IX 7 product had a melting point of 148150 C., and the formulawhich was confirmed by nuclear magnetic resonance spectral examinationand the following elemental analysis (percent by weight) Found: C,69.50; H, 5.95; S, 12.36. C H O S: C, 69.20; H, 6.20; S, 12.32.

This process is successfully repeated utilizing other solvent media: oneconsisting of 10* parts by volume of the t-butanol and 90 parts byvolume of the dimethyl sulfoxide; asecond consisting of 25% 'by volumeof t-butanol to 75% of the DMSO; and a third consisting only of dimethylsulfoxide.

Calculated for Example X A solution of two millimoles of anthraquinonein 25 milliliters of an 80-20 mixture (by volume) of dimethyl sulfoxideand tertiary butyl alcohol containing 4 millimoles of potassium tertiarybutoxide was maintained under an atmosphere of nitrogen and stirredgently for 1 hour. Water was added to the reaction mixture and theproduct was recovered by the procedure of Example VIII. A yield of 1.64millimoles was thus obtained of the dimethyl sulfoxide adduot, meltingpoint 156156.5 C. and formula v onzsocng Elemental analysis.Found: C,66.91; H, 5.14; S, 11.75. Calculated for C H O S: C, 67.11; H, 4.93; S,11.20

Example XI Proceding as described above but using only one-tenth (0.4millimole) of the foregoing amount of potassium tertiary butoxide forthe 2.0 millimoles of fiuorenone, and a reaction period of 4 hours atroom temperature instead of 5 minutes, the amount of dimethyl sulfoxideadduct obtained was 1.36 millimoles, a yield of 68%.

Example XII Five hunderd eighty tmg. (2.5 mole) of phenylp-tolylsulfonewere dissolved in 11 ml. dimethyl sulfoxide (DMSO) and 2 ml. t-butylalcohol. Under a nitrogen atmosphere 560 mg. of sublimed potassiumt-butoxide, (5 10 mole) were added. While stirring under a nitrogenatmosphere at room temperature, 1 ml. of benzaldehyde in 4 ml. DMSO and1 ml. t-butyl alcohol were added from a burette over the course of 10minutes. The reddish solution turned green. The stirring was continuedfor 30 more minutes. Then 50 ml. of water were added, yielding acolorless crystalline precipitate. This was filtered and washed withwarm absolute ethanol, yielding 320 mg. of purep-(phenylsulfonyl)-stilbene, M.P. 184-185 (40% yield). It can berecrystallized from cholorform.

Analysis.--Calculated for C H O S: C, 74.99%; H, 5.03%; S, 9.99%. Found:C, 74.82%; H, 5.01%; S, 10.01%.

The nuclear magnetic resonance spectrum (in CDCl 60 mc./sec.) does notshow any saturated protons. The protons in the aromatic and olefinicregion appear in the ratio 411022.

Example XIII The following stilbenes have been prepared in a similarmanner, starting fromphenyl-patolylsulfone and the corespondingaldehydes. Their structures are supported by analysis, infraredabsorption and NMR spectra.

32% yield, colorless crystals, M.P. 202203.

Analysis.-Calculated for C H O S: C, 71.99; H, 5.18; S, 9.13. Found: C,71.77; H, 5.02; S, 9.36.

5.5% yield colorless crystals, M.P. 188.

Analysis.-Calculated for C H O S: C, 69.22; H, 4.43; S, 8.78. Found: C,69.10; H, 4.27; S, 8.99.

11% yield yellow crystals, M.P. 250251 C.

Analysis.-Calculated Ifor C H NO S: C, 72.71; H, 5.82; N, 3.85. Found:C, 72.51; H, 5.72; N. 4.09.

M.P. 315 C.

Analysis.Calculated: C, 67.82; H, 4.38; S, 13.9. Found: C, 67.71; H,4.68; S, 13.43.

Example XIV The processes of Examples X and XIII are repeated, using thefollowing alkali metal bases in lieu of potassium t-butoxide, each attwo different concentrations, 0.1 and 3.0 moles per mole of aldehyde:lithium teritary b-utoxide, sodium ethoxide, potassium hydroxide, sodiumoxide,

lithium methoxide, and sodium hydride. In each instance the reactionproceeds smoothly and the desired product is obtained.

What is claimed is:

1. Compounds having the formula wherein R is selected from the groupconsisting of phenyl and lower 'alkoxy-subst-ituted phenyl, -R isselected from the group consisting of phenyl, lower alkyl-substitutedphenyl, phenylsulfonyl and methylsulfinyl, and R" is selected from thegroup consisting of phenyl, lower alkylsubstituted phenyl andphenylsulfonyl.

2. A compound laCCOldlIlg to claim 1 wherein R is paramethoxyphenyl andeach of R and R is phenyl.

3. A compound according to claim 1 wherein each of R, R and R" isphenyl.

4. A process for the condensation of benzaldehydes which have no acidicalpha-hydrogen atom, with active methylene compounds selected from thegroup consisting of phenyl alkyl ketones; ketohexamethylene; compoundshaving the formula RR"C H wherein R is selected from the groupconsisting of phenyl, lower alkyl-su bstituted phenyl, phenylsulfony-land methylsulfinyl, and R" is selected from the group consisting ofphenyl, lower alkylsubstituted phenyl and phenylsulfonyl; and compoundshaving the formula R'CH wherein R is selected from the group consistingof methylsulfinyl and substituted phenyl, wherein the substituent isacid-strengthening, which process pompri ses interracting the saidaromatic aldehyde and the said active methylene compound, attemperatures substantially between 20 and 80 C., in an alkaline mediumconsisting essentially of dimethyl sulfoxide and a strong base selectedfrom the class consisting of alkali metal oxides, alkali metalhydroxides, alkali metal alkoxides, and alkali metal hydrides.

5. A process for the condensation of benzaldehydes which have no acidicalphahydrogen atom with an active methylene compound having the formulaRR"CH wherein R is selected from the group consisting of phenyl, loweralkyl-substituted phenyl, phenylsulfonyl and methylsulfinyl and R" isselected from the group consisting of phenyl, lower alkyl-substitutedphenyl and phenylsulfonyl, which process comprises interreacting thesaid aldehyde and the said active methylene compound, at temperaturessubstantially between 30 and 60 C., in an alkaline medium consistingessentially of dimethyl sulfoxide and an alkali metal alkoxide, andrecovering the condensed sulfoxide product.

10 v 6. The process of claim 5 wherein the sul'foxide product is heatedto drive ofi -C-H SOH and the resulting olefin is recovered.

7. A process according to claim 5 wherein the active methylene compoundis ldiphenylmethane.

8. A process for the preparation of stilbene derivatives which comprisesinterreacting benzaldehydes which have no acidic alphahydrogen atom andan active methylene compound having the formula R'CH wherein R isselected from the group consisting of methylsulfinyl and substitutedphenyl where-in the substituent is acidstrengthening, at temperaturessubstantially between 20 and 40 C., in )an alkaline medium consistingessentially of dimethyl sulfoxide and between 0 and about by volume oftertiary butyl alcohol together with from about 0.1 to about 3.0 Lmoles(based on the said aldehyde) of an alkali metal tertiary but-oxide.

9. A process according to claim 8 wherein the active methylene compoundis phenyl p-tolyl sul-fone.

References Cited by the Examiner UNITED STATES PATENTS 2,145,501 1/1989Waterman et al. 2606 69 2,189,771 2/1940 Smith @-669 3,043,879 7/ 1962Davis et al. 2 60--*607 3,045,051 7/ 1962 Coma et al. 260--607 CHARLESB. PARKER, Primary Examiner.

DANIEL D. HORWITZ, Examiner.

DELBERT R. PHILLIPS, Assistant Examiner.

1. COMPOUNDS HAVING THE FORMULA
 4. A PROCESS FOR THE CONDENSATION OFBENZALDEHYDES WHICH HAVE NO ACIDIC ALPHA-HYDROGEN ATOM, WITH ACTIVEMETHYLENE COMPOUNDS SELECTED FROM THE GROUP CONSISTING OF PHENYL ALKYLKETONES; KETOHEXAMETHYLENE; COMPOUNDS HAVING THE FORMULA R''R"CH2WHEREIIN R'' IS SELECTED FROM THE GROUP CONSISTING OF PHENYL, LOWERALKYL-SUBSTITUTED PHENYL PHENYLSULFONYL AND METHYLSULFINYL,AND R" ISSELECTED FROM THE GROUP CONSISTING OF PHENYL, LOWER ALKYLSUBSTITUTEDPHENYL AND PHENYLSULFONYL; AND COMPOUNDS HAVING THE FORMULA R''CH3WHEREIN R'' IS SELECTED FROM THE GROUP CONSISTING OF METHYLSULFINYL ANDSUBSTITUTED PHENYL, WHEREIN THE SUBSTITUENT IS ACID-STRENGTHENING, WHICHPROCESS COMPRISES INTERRACTING THE SAID AROMATIC ALDEHYDE AND THE SAIDACTIVE METHYLENE COMPOUND, AT TEMPERATURES SUBSTANTIALLY BETWEEN 20* AND80*C., IN AN ALKALINE MEDIUM CONSISTING ESSENTIALLY OF DIMETHYLSULFOXIDE AND STRONG BASE SELECTED FROM THE CLASS CONSISTING OF ALKALIMETAL OXIDES, ALKALI METAL HYDROXIDES, ALKALI METAL ALKOXIDES, ANDALKALI METAL HYDRIDES.